Cardiac regeneration with bone marrow derived stem cells (BMSCs) is a novel approach to repair the infarcted myocardium. Unfortunately, stem cell homing to the infarcted myocardium and proliferation are very inefficient, leading to only limited differentiation into cardiac myocytes. This approach is, therefore, not fully effective for recovery of heart function. Once stem cells reach the infarcted myocardium, they are exposed to an ischemic environment in which their survival is in jeopardy. The stage of infarction is an important consideration as scar tissue forms when the infarction is advanced. Our preliminary data show that CXCR4 overexpressing MSCs (CXCR4+-MSCs) are an optimal subpopulation of BMSCs that are attracted to the infarcted myocardium and contribute to increased angiomyogenesis. Moreover, CXCR4+-MSCs secrete anti- fibrotic factors and survival proteins, which mediate enhanced engraftment and proliferation. Our preliminary data support the hypothesis that newly formed cardiomyocytes derived from CXCR4+-MSCs can proliferate profusely upon pharmacological interventions and possibly expedite the process of repopulating the infarcted myocardium.The following hypotheses will be tested. Hypothesis 1: CXCR4+-MSCs repair the infarcted myocardium by releasing anti-fibrotic factors and survival proteins. In Aim 1 we will test the sub-hypotheses that: 1A, Overexpression of CXCR4+ results in enhanced MSC survival and engraftment in the infarcted myocardium; 1B, CXCR4+-MSCs attenuate remodeling post-myocardial infarction by releasing anti-fibrotic enzymes; and 1C, CXCR4+-MSCs reduce ischemic injury by upregulation of Akt. Hypothesis 2: CXCR4+ expression on MSCs promotes their angiomyogenic potential. In Aim 2 we will test the sub-hypotheses that: 2A, CXCR4+-MSCs promote angiogenesis by releasing angiogenic factors; 2B, CXCR4+-MSCs express cytoprotective or survival proteins which enhance their myogenic potential in the infarcted myocardium. Hypothesis 3: Regeneration of infarcted myocardium is maximized by disintegration of scar tissue and proliferation of newly formed myocytes. In Aim 3 we will test the hypotheses that: 3A, Cardiac scar formation in the infarcted area retards the engraftment of MSCs; 3B, In response to a potent cell cycle reentry stimulant, enhanced myogenesis from CXCR4+-MSCs leads to repopulation of the infarcted area. These therapeutic approaches have the potential to be developed into therapies for human myocardial infarction. PUBLIC HEALTH RELEVANCE: CXCR4 stem cells are an optimal subtype of BMSC for cardiac repair; the anti-fibrotic effects of CXCR4+- MSCs and use of potent cell cycle reentry stimulants are novel and innovative. It is expected that effective engraftment and proliferation of CXCR4+-MSCs in ischemic tissue will profusely populate the infarcted area, improving cardiac function, and that knowledge gained from this work will lead to new strategies to treat the myocardial infarction.